Nuclear Receptor Program (NRP) PROJECT SUMMARY The main goal of the Nuclear Receptor (NR) program is to promote rapid translation of basic discoveries on nuclear receptor dependent and epigenetic (coregulator-mediated) mechanisms of transcriptional regulation of carcinogenesis to the clinic for development of novel prognostic markers for specific subsets of malignancies, and for the identification of novel molecular targets for prevention and therapeutic intervention. The program has 18 funded Research Members and 2 Clinical Members. Faculty includes members of the Departments of Molecular and Cellular Biology, Medicine, and Pharmacology. The NR program is lead by Drs. Orla Conneely, an internationally recognized leader in NRs, and Suzanne Fuqua, who brings extensive translational research experience in estrogen receptors in breast cancer to the program as the co-leader. The NR program is organized around two main themes: 1. the identification of NRs which contribute to cancer pathogenesis and progression, disclosure of their molecular mechanism of action, and evaluation of their potential as novel targets for therapeutic intervention in cancer, and 2. the characterization of NR coregulator- dependent epigenetic mechanisms of cancer development. The program has a total of $18.0 million in cancer- related funding (of which $16.1 million is peer-reviewed), and includes $1.2 million in funding from the NCI. In the last 4 years members of the program published 227 cancer-related publications in peer-reviewed journals of which 27% represented intra-programmatic collaborations, 36% inter-programmatic, and 49% inter- institutional collaborations. Major accomplishments include: 1) elucidation of the role of the COUP-TFI NR in prostate cancer development and metastasis, 2) the role of the FXR and SHP NRs in liver tumorigenesis, 3) the regulation of hematopoietic stem cells by the orphan NR4A family, 4) the novel role of Mi2/NURD components in the epigenetic control of breast cancer metastasis, and 5) the promotion of breast, prostate, and lung cancers by SRC-3, along with the design, synthesis and use of SRC-3 targeting agents to treat these important adult cancers. Translational efforts include: 1) the identification of YAP-1 and IQGAP1 as novel biomarkers for liver cancer, 2) the use of selective estrogen receptor modulators in human bladder cancer, 3) the therapeutic potential of CARM1 coregulator inhibition, 4) the development of first-in-class coactivator therapies for breast and lung cancer, and 5) investigator-initiated clinical trials of androgen deprivation and androgen synthesis inhibitors in prostate cancer.